Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2
Clinical Phenotype: Alzheimer's Disease
Coding/Non-Coding: Both
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Genomic Region: Chromosome 21

Findings

This mutation was identified in a screen of patients with early onset Alzheimer’s disease from 28 French hospitals (Lanoiselée et al., 2017). Families were included when at least two first-degree relatives, spanning two generations, suffered from early onset AD with an age of onset of 65 years or younger. Age at onset in this pedigree (EXT 814) ranged from 50 to 54 years, and disease duration ranged from eight to 10 years. The mutation was identified in a single family member by analyzing the APP locus on chromosome 21 using quantitative multiplex PCR of short fluorescent fragments (QMPSF)—a method that simultaneously amplifies multiple short genomic sequences. This individual had an APOE3/E3 genotype.

APP duplications are rare or absent from the general population (Sharp et al., 2005). However, they may be a relatively common cause of familial AD, at least in some populations. This may be due to APP being in a recombination hotspot that harbors multiple low copy repeats (Sleegers et al., 2006; Rovelet-Lecrux et al., 2006).

Neuropathology
Neuropathological data are unavailable, but cerebrospinal fluid biomarkers, including Aβ42, tau and phospho-tau 181, in the proband were consistent with AD pathology (Lanoiselée et al., 2017).

Biological Effect
The biological effect of this specific APP duplication is unknown, but a study of multiple carriers of APP duplications showed that, as expected, the median levels of APP mRNA in blood were approximately 1.4-fold higher in carriers compared with non-carriers (Pottier et al., 2012). However, variability between duplications and individual carriers suggests other factors, such as the specific genes included in the duplication, may modulate expression (e.g., Lott and Head, 2019).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS1-M

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Duplication 5.9Mb (French): Similar to other APP duplications known to be pathogenic, although exact DNA changes varied.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Duplication 5.9Mb (French): Data unavailable for this specific duplication, but pooled data reveal APP duplications increase APP dosage.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Duplication 5.9Mb (French): Mutation encompasses the APP gene, a mutational hotspot and a gene known to play a well-established functional role in AD.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 04 Mar 2023

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References

Paper Citations

Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, Pertz LM, Clark RA, Schwartz S, Segraves R, Oseroff VV, Albertson DG, Pinkel D, Eichler EE. Segmental duplications and copy-number variation in the human genome. Am J Hum Genet. 2005 Jul;77(1):78-88. Epub 2005 May 25 PubMed.
Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C. APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain. 2006 Nov;129(Pt 11):2977-83. Epub 2006 Aug 18 PubMed.
Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. Epub 2005 Dec 20 PubMed.
Pottier C, Wallon D, Lecrux AR, Maltete D, Bombois S, Jurici S, Frebourg T, Hannequin D, Campion D. Amyloid-β protein precursor gene expression in alzheimer's disease and other conditions. J Alzheimers Dis. 2012;28(3):561-6. PubMed.
Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.

Mutations

APP Duplication 5.9Mb (French)

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